Analgesic and anti-inflammatory compositions comprising diphenhydramine and methods of using same

ABSTRACT

Novel pharmaceutical compositions of matter are provided comprising analgesic/non-steroidal anti-inflammatory drugs and diphenhydramine and methods of using said compositions to elicit an enhanced analgesic and/or anti-inflammatory response in mammalian organisms in need of such treatment.

This application is a division of application Ser. No. 711,525, filedMar. 14, 1985) now 4,585,783 which is a division of Ser. No. 578,288,filed Feb. 8, 1984, now U.S. Pat. No. 4,522,826.

BACKGROUND OF THE INVENTION

The present invention relates generally to novel pharmaceuticalcompositions of matter comprising diphenhydramine and one or morenon-steroidal anti-inflammatory drugs (NSAID) having analgesic andanti-inflammatory properties, and to methods of using said compositionsto elicit an enhanced analgesic or anti-inflammatory response inmammalian organisms in need of such treatment.

Non-narcotic analgesics, most of which are also known as non-steroidalanti-inflammatory drugs (NSAID), are widely administered orally in thetreatment of mild to severe pain. Within this class, the compounds varywidely in their chemical structure and in their biological profiles ananalgesics, anti-inflammatory agents and antipyretic agents. Aspirin,acetaminophen and phenacetin have long been among the most commonly usedmembers of this group; more recently, however, a large number ofalternative non-narcotic agents offering a variety of advantages overthe earlier drugs have been developed. Tolerance or addiction to thesedrugs is not generally a problem with their continuous use in thetreatment of pain or in the treatment of acute or chronic inflammatorystates (notably, rheumatoid arthritis and osteoarthritis); nevertheless,these drugs generally have a higher potential for adverse side-effectsat the upper limits of their effective dose ranges. Moreover, above eachdrug's upper limit or ceiling, administration of additional drug doesnot usually increase the analgesic or anti-inflammatory effect. Amongthe newer compounds in the non-narcotic analgesic/nonsteroidalanti-inflammatory group are compounds such as diflunisal (Dolobid®),zomepirac sodium (Zomax®), ibuprofen (Motrin®), naproxen (Naprosyn®),fenoprofen (Nalfon®), piroxicam (Feldene®), flurbiprofen, mefenamic acid(Ponstel®) and sulindac. See also Physicians' Desk Reference, 35thedition, 1981, and The Merck Index, ninth edition, Merck & Co., Rahway,N.J. (1976), for information on specific nonsteroidal anti-inflammatoryagents. Also see, generally, Wiseman, "Pharmacological Studies with aNew Class of Nonsteriodal Anti-Inflammatory Agents--The Oxicams--WithSpecial Reference to Piroxicam (Feldene®), The American Journal ofMedicine, Feb. 16, 1982: 2-8; Foley et al, The Management of CancerPain, Volume II--The Rational Use of Analgesics in the Management ofCancer Pain, Hoffman-LaRoche Inc., 1981; and Cutting's Handbook ofPharmacology, sixth edition, ed. T. Z. Czaky, M.D.,Appelton-Century-Crofts, New York, 1979, Chapter 49: 538-550, includingstructural formulas for representative group members.

Diphenhydramine[2-(diphenylmethoxy)-N,N-dimethylethylamine] is also awell-known therapeutic agent in long standing use by clinicians as anantihistamine. It is recognized in both the U.S.P. and N.F. as anofficial antihistamine of the ethanolamine (or aminoalkyl ether) typeand is available as the hydrochloride salt in Benadryl® and variousalternative sources in 50 milligram delayed action tablets, 25 and 50milligram capsules, elixirs (12.5 mg/5 ml) and sterile solution forinjection (10 mg/ml). Depending upon the therapeutic indication,diphenhydramine is recommended in single or divided doses of between12.5 to 50 milligrams with a maximum daily dosage not to exceed 300milligrams. The antihistaminic activity of diphenhydramine is directlyattributable to its competitionn with histamine for cell receptor siteson effector cells although diphenhydramine also demonstrates, inaddition, a number of therapeutic applications attributable to centralactions unrelated to histamine antagonism. Antihistaminic indicationsfor diphenhydramine include perennial and seasonal allergic rhinitis,vasomotor rhinitis, allergic conjunctivitis, urticaria and as adjunctivetherapy for anaphylactic reactions. Central nervous system side effects(non-histaminic actions) which have been capitalized upon includeprophylactic and active treatment of motion sickness and, more broadly,as an antinauseant and in the treatment of mild forms of Parkinsonism.Diphenhydramine demonstrates both stimulant and depressant effects onthe central nervous system although stimulation is only occasionallyseen in patients given conventional doses with accompanyingrestlessness, nervousness and inability to sleep. The more predominantsedative action of diphenhydramine has been beneficially capitalizedupon with the usage of diphenhydramine as a somnolent when employed atthe maximum 50 milligrams dose in both prescription and over-the-counterforms. In this regard, it is noted that the Food and Drug Administrationannounced in the November 1983 FDA Drug Bulletin (Vol. 13, No. 3) thatdiphenhydramine (50 mg.) may now be marketed over-the-counter as anighttime sleep aid.

An early study (1958) investigated the properties of diphenhydramine asa pre-anesthetic medication. (Lear, et al., "Comparative Studies ofTranquilizers Used in Anesthesia." JAMA, 1958, 166(12): 1438-1443). Theauthors concluded that diphenhydramine, particularly when used incombination with meperidine, provides beneficial preoperative sedationwith less overall depression then previously experienced with the use ofroutine doses or narcotics and barbiturates.

Diphenhydramine has also been investigated with varying results withrespect to its potential as a weak analgesic. Diphenhydraminehydrochloride when introduced intravenously has been reported as beinguseful in obstetric analgesia alone and in combination with alcohol. SeeCappe, B. E. et al, "Recent Advances in Obstetric Analgesia", JAMA,1954, 154(5); 377-379. Campos et al in a comparative study found thatdiphenhydramine given either orally or intramuscularly could not bedistinguished from placebo in patients with postoperative fractures orsomatic pain. ["The Analgesic and Hypothermic Effects of Nefopam,Morphine, Aspirin, Diphenhydramine and Placebo", Journal of Clin.Pharmacology, January, 1980, pp. 42-49.]

Albal and Chandorkar studied an injectable combination analgesicconsisting of analgin 375 mg, a centrally acting analgesic, diazepam 2.5mg, and diphenhydramine 20 mg, and found relief from pain. They did not,however, study the unique contribution of diphenhydramine. [Albal, M.V., and Chandorkar, A. G. "Clincal Evaluation of Sedyn-a-Forte, anAnalgesic Injection Containing Analgin, Diphenhydramine and Diazepam."Indian Journal of Ophthalmology, 1982, 30: 271-273]. [Note: analginreferred to in the foregoing study is dypyrone; see The Merck Index, p.3361, 1976.]

While diphenhydramine has been investigated with respect to its weakanalgesic properties, it is also evident from the foregoing that itssedative and local anesthetic properties may, in part, account for itssuspected potential for relieving pain. In the Lear et al, supra, studydiphenhydramine at 25 to 50 milligram doses was insufficient as apreanesthetic medication and combination with meperidine (a narcoticanalgesic) was proposed to optimize the potential beneficial effects ofdiphenhydramine as an analgesic.

Hydroxyzine, which is a minor tranquilizer with antihistaminic activity,has been evaluated as an analgesic. Beaver and Feise found that, "Thisstudy unequivocally demonstrates analgesic activity for a 100 mg dose ofintramuscular hydroxyzine in the general range of that produced by 8 mgof morphine. In addition, the analgesic activity of hydroxyzine appearsadditive with that of morphine when the two drugs are given together."The findings of the study do not indicate synergistic activity. (Beaver,W. T. & Feise, G. "Comparison of the Analgesic Effects of Morphine,Hydroxyzine, and Their Combination in Patients with Postoperative Pain."Advances in Pain Research and Therapy, 1976, 1: 553-557)

Only recently have animal studies been conducted in which the analgesicactivity of diphenhydramine has been investigated. Bluhm, et al., in astudy conducted on mice, found that diphenhydramine potentiatesmorphine, a centrally acting drug, when administered parenterally. Oraladministration of drugs was not studied. (Bluhm, et al., "Potentiationof Opioid Analgesia By H₁ and H₂ Antagonists." Life Sciences, 1982, 31:1229-1232)

Diphenhydramine has not been heretofore proposed for use in combinationwith any of the newer nonsteroidal analgesic/anti-inflammatory agents(i.e., excluding aspirin, acetaminophen and phenacetin). In U.S. Pat.No. 4,420,483 issued Dec. 13, 1983, the present applicants disclose thehastening of the onset of analgesic and anti-inflammatory responsesobserved with several different nonsteroidal anti-inflammatory agents aswell as the enhancement of the analgesic and anti-inflammatory responsewith such agents by the concomitant administration of caffeine as apotentiating adjuvant.

Applicants have now surprisingly found that diphenhydraminesynergistically enhances the analgesic and anti-inflammatory propertiesof such non-steroidal anti-inflammatory drugs (NSAID).

SUMMARY OF THE INVENTION

It is, therefore, a primary object of the present invention to provide anovel pharmaceutical composition of matter for promoting an enhancedanalgesic and anti-inflammatory response in a mammalian organism in needof such treatment comprising an analgesically and anti-inflammatorilyeffective amount of a non-steroidal anti-inflammatory drug (NSAID) incombination with diphenhydramine or a pharmaceutically acceptable saltthereof.

It is a further object of the present invention to provide methods forobtaining analgesic and anti-inflammatory responses in mammals,including humans, by the administration of preselected dosages of anon-steroidal anti-inflammatory agent, with diphenhydramine.

A still further object of the present invention is to provide apharmaceutical composition of matter for obtaining a synergisticanalgesic and anti-inflammatory response in mammals in which thecomposition comprises an analgesically and anti-inflammatorily effectiveamount of a selected NSAID and a synergistic amount of diphenhydramineoptionally in the presence of a pharmaceutically acceptable inertcarrier.

Another object of the invention is to provide suitable dosage unit formsof one or more NSAID's and diphenhydramine adapted for, e.g., oral,rectal, parenteral, topical, etc., administration and useful in thetreatment, management and mitigation of pain and/or inflammation.

These and other similar objects, advantages and features areaccomplished accordng to the products, compositions and methods of theinvention comprised of a non-steroidal anti-inflammatory drug oranalgesic and diphenhydramine and analgesic and anti-inflammatorymethods employing same.

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE of Drawing is a plot of dose of diphenhydramine versus doseof ibuprofen in the phenylquinone writhing assay to indicate the numberof mice protected.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

It has now been unexpectedly found in accordance with the presentinvention that the analgesic and anti-inflammatory effects observed uponthe administration of a non-narcotic analgesically active non-steroidalanti-inflammatory drug (i.e., analgesic/NSAID), can be synergisticallyenhanced by the co-administration of diphenhydramine or a non-toxicpharmaceutically acceptable salt thereof.

As used herein, the terms "synergism" and "synergistic" are used todescribe the potentiated analgesic and anti-inflammatory responseselicited by the co-administration of an analgesic NSAID anddiphenhydramine (or pharmaceutically acceptable salts thereof). Morespecifically, these terms as used herein are defined in contradistinctonto merely additive effects. The effects of two compounds are additive ifthe response to a dose of both in combination does not change when aportion of one component is removed from the mixtures and replaced by anequipment portion of the other. If such substitution increases theresponse, the mixing together of the compounds is said to potentialstheir effects and synergism exists.

The non-narcotic analgesics/nonsteroidal anti-inflammatory drugs for usein the compositions and methods of the present invention can be selectedfrom the following categories:

(1) the propionic acid derivatives;

(2) the acetic acid derivatives;

(3) the fenamic acid derivatives;

(4) the biphenylcarboxylic acid derivatives; and

(5) the oxicams.

The term "selected NSAID" as used herein is intended to mean anynon-narcotic analgesic/non-steroidal anti-inflammatory compound fallingwithin one of the five structural categories above but excludingaspirin, acetaminophen and phenacetin.

While some of these compounds are primarily used at the present time asanti-inflammatory agents and others are primarily used as analgesics, infact all of the contemplated compounds have both analgesic andanti-inflammatory activity and can be used at appropriate dosage levelsfor either purpose in the compositions and methods of the presentinvention. The compounds in groups (1) through (4) typically contain acarboxylic acid function; however, those acids are sometimesadministered in the form of their pharmaceutically acceptable acidaddition or alkali metal salts, e.g., sodium salts.

The propionic acid derivatives for use herein include, but are notlimited to, ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen,fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin,pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen,tiaprofenic acid, fluprofen and bucloxic acid. Structurally relatedpropionic acid derivatives having similar analgesic andanti-inflammatory properties are also intended to be encompassed by thisgroup. Presently preferred members of the propionic acid group includeibuprofen, naproxen, flurbiprofen, fenoprofen, ketoprofen and fenbufen.

Thus, "propionic acid derivatives" as defined herein are non-narcoticanalgesics/nonsteriodal anti-inflammatory drugs having a free--CH(CH₃)COOH or --CH₂ CH₂ COOH group (which optionally can be in theform of a pharmaceutically acceptable salt group, e.g. --CH(CH₃)COO⁻ Na⁺or --CH₂ CH₂ COO⁻ Na⁺), typicaly attached directly or via a carbonylfunction to a ring system, preferably to an aromatic ring system.

The acetic acid derivatives for use herein include, but are not limitedto, indomethacin, sulindac, tolmetin, zomepirac, diclofenac,fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac and oxpinac. Structurallyrelated acetic acid derivatives having similar analgesic andanti-inflammatory properties are also intended to be encompassed by thisgroup. Presently preferred members of the acetic acid group includetolmetin sodium, zomepirac sodium, sulindac and indomethacin.

Thus, "acetic acid derivatives" as defined herein are non-narcoticanalgesics/nonsteroidal anti-inflammatory drugs having a free --CH₂ COOHgroup (which optionally can be in the form of a pharmaceuticallyacceptable salt group, e.g., --CH₂ COO⁻ Na⁺), typically attacheddirectly to a ring system, preferably to an aromatic or heteroaromaticring system.

The fenamic acid derivatives for use herein include, but are not limitedto, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acidand tolfenamic acid. Structurally related fenamic acid derivativeshaving similar analgesic and anti-inflammatory properties are alsointended to be encompassed by this group. Presently preferred members ofthe fenamic acid group include mefenamic acid and meclofenamate sodium(meclofenamic acid, sodium salt).

Thus, "fenamic acid derivative" as defined herein are non-narcoticanalgesics/nonsteroidal anti-inflammatory drugs which contain the basicstructure ##STR1## which can bear a variety of substituents and in whichthe free --COOH group can be in the form of a pharmaceuticallyacceptable salt group, e.g., --COO⁻ Na⁺.

The biphenylcarboxylic acid derivatives for use herein include, but arenot limited to, diflunisal and flufenisal. Structurally relatedbiphenylcarboxylic acid derivatives having similar analgesic andanti-inflammatory properties are also intended to be encompassed by thisgroup. Preferred members of this group are diflunisal and flufenisal.

Thus, "biphenylcarboxylic acid derivative" as defined herein arenon-narcotic analgesics/nonsteroidal anti-inflammatory drugs whichcontain the basic structure ##STR2## which can bear a variety ofsubstituents and in which the free --COOH group can be in the form of apharmaceutically acceptable salt group, e.g. --COO⁻ Na⁺.

The oxicams for use herein include, but are not limited to, piroxicam,sudoxicam, isoxicam and CP-14, 304. Structurally related oxicams havingsimilar analgesic and anti-inflammatory properties are also intended tobe encompassed by this group. A preferred member of this group ispiroxicam.

Thus, "oxicams" as defined herein are non-narcoticanalgesics/nonsteroidal anti-inflammatory drugs which have the generalformula ##STR3## wherein R is an aryl or heteroaryl ring system.

The precise amount of non-narcotic analgesic/non-steroidalanti-inflammatory drug for use in the present compositions will varydepending, for example, on the specific drug chosen, the dosage formthereof, i.e., standard versus sustained release, the condition forwhich the drug is administered and the size and kind of the mammal.

For humans, typical effective analgesic/anti-inflammatory amounts ofpresently preferred NSAIDs for use in unit dose compositions of theinvention are about 125 to 500 mg diflunisal, about 25 to 100 mgzomepirac sodium, about 50 to 400 mg ibuprofen, most preferably 100-400mg, about 125 to 500 mg naproxen, about 25 to 50 mg flurbiprofen, andabout 50 to 200 mg fenoprofen, about 10 to 20 mg piroxicam, about 125 to250 mg mefenamic acid, about 100 to 400 mg fenbufen or about 25 to 50 mgketoprofen; however, greater or lesser amounts can be employed ifdesired.

For example, in one preferred embodiment of this invention, the desiredtherapeutic response for ibuprofen therapy in mild to moderate pain isgenerally observed at 200 to 600 milligrams of ibuprofen every 4 to 6hours as necessary up to about 2400 milligrams total daily dose.Consistent with the synergistic results achieved with theibuprofen/diphenhydramine compositions and methods of the presentinvention, the desired analgesic and/or anti-inflammatory response canbe achieved upon the administration of ibuprofen and diphenhydraminewherein the ibuprofen component can be administered at reduced levels ofbetween about 50 to 400 milligrams of ibuprofen and, most preferably,100 to 400 milligrams. Alternatively, the usual dosage regimen foribuprofen may be followed when the composition of the present inventionadditionally comprising diphenhydramine is employed whereby the levelsof analgesia and anti-inflammatory results are enhanced.

The amount of diphenhydramine present in the compositions according tothe present invention ranges between about 12.5 to 50 milligrams and,preferably, between about 25 to 50 milligrams.

In any event, the amounts of NSAID and diphenhydramine to beadministered in a total daily dose should not exceed the generallyrecognized as safe limits established for the particular NSAID anddiphenhydramine when administered alone for their respective usualtherapeutic indications.

In the compositions and methods of the invention, an NSAID anddiphenhydramine may be co-administered in the same composition orconcomitantly administered separately.

In accordance with the practices of the present invention, theNSAID/diphenhydramine compositions may be administered in admixture withsuitable pharmaceutical diluents, carriers or other excipients(collectively referred to as "carrier" materials) suitably selected withrespect to the intended route of administration and conventionalpharmaceutical practices. For instance, for oral administration in theform of tablets or capsules, the active drug components may be combinedwith any oral non-toxic pharmaceutically acceptable inert carrier suchas lactose, starch, sucrose, cellulose, magnesium stearate, dicalciumphosphate, calcium sulfate, mannitol and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents and coloring agents can also be incorporated in the mixture.Suitable binders include starch, gelatin, natural sugars, cornsweeteners, natural and synthetic gums such as acacia, sodium alginate,carboxymethylcellulose, polyethylene glycol and waxes. Among thelubricants there may be mentioned for use in these dosage forms, boricacid, sodium benzoate, sodium acetate, sodium chloride, etc.Disintegrators include, without limitation, starch, methylcellulose,agar, bentonite, guar gum, etc. Sweetening and flavoring agents andpreservatives can also be included where appropriate. Similarly,injectable dosage units may be utilized to accomplish intravenous,intramuscular or subcutaneous administration and, for such parenteraladministration, suitable sterile aqueous or non-aqueous solutions orsuspensions, optionally containing appropriate solutes to effectuateisotonicity, will be employed.

Moreover, in accordance with another preferred embodiment of the presentinvention, where therapeutic indications warrant, such as in the casewhere the level of pain and inflammation associated with the disordermay interfere with normal sleep latency and maintenance dosage regimensmay be contemplated, the NSAID/diphenhydramine compositions of theinvention may be formulated for administration at bedtime as ananalgesically and anti-inflammatorily effective nighttime sleep aid.Accordingly, the NSAID and diphenhydramine components of the compositionmay be formulated in dosage unit form to provide a dose ofdiphenhydramine (compared to the amount necessary to promote the desiredsynergistic response) to take advantage of the sleep-inducing sideeffect of diphenhydramine.

In another preferred embodiment, the advantageous analgesic andanti-inflammatory compositions of the invention may be formulated insustained release form to provide the rate controlled release of eitheror both of the components to optimize analgesic and anti-inflammatoryresponse while minimizing undesirable side effects in, for example,patients unusually sensitive to either or both of the active drugs.Suitable dosage forms for sustained release include layered tabletscontaining layers of varying disintegration rates or controlled releasepolymeric matrices impregnated with the active components and shaped intablet form or capsules containing such impregnated or encapsulatedporous polymeric matrices. Thus, with respect to such layered tablets,one layer may contain an initial dosing amount of, for example,ibuprofen, of 400 milligams and 25 milligrams of diphenhydramine,whereas two or more further layers may contain, for instance, 100milligram of ibuprofen and 15 to 25 milligrams of diphenhydramine to bereleased serially every 4 to 6 hours consistent with the normal dosageschedule. Another advantage afforded the analgesic and anti-inflammatorycompositions of the present invention by the inclusion of thediphenhydramine component is that gastrointestinal disturbances, whichare the most frequent adverse reactions reported for non-steroidalanti-inflammatory drugs, including complaints involving abdominaldistress, epigastric pain, indigestion, nausea and vomiting may often byminimized or, at least, reduced. The foregoing advantage is both afunction of the synergism exhibited by the NSAID/diphenhydraminecomposition which allows for the use of the NSAID component inquantities substantialy less than dosages presently considered necessaryas an analgesic or anti-inflammatory agent in humans, which lower dosesresult in lowering the incidence or severity of undesirable sideeffects, as well as the presence of diphenhydramine contributingvaluable antinauseant and antiemetic properties to the composition.

In patients particularly susceptible to the tendency of either the NSAIDor diphenhydramine to promote drowsiness or, in the extreme, sedationand, otherwise, in ambulatory patients where drowsiness and/or sedationmay represent untoward side effects, the compositions of the presentinvention may further include caffeine to counteract drowsiness symptomsand to further take advantage of the potentiated analgesic andanti-inflammatory response effectuated by the addition of caffeine asdisclosed in applicants U.S. Pat. No. 4,420,483.

EXAMPLE 1 Pharmacologic Test for Synergism--Ibuprofen/Diphenhydramine

The unexpected synergistic analgesic effect of the addition ofdiphenhydramine to ibuprofen is evidenced by tests conducted on mice.Blue Spruce Farm male mice weighing 18-28 grams at the time of testingare used throughout. All mice are dosed orally by gavage with ibuprofenand/or diphenhydramine. The formulation of each test article is asolution or suspension in 0.25% methylcellulose manufactured by FisherScientific Company. A dosing volume of 10 ml/mg is used. All doses arecoded and the test is performed under a code not known to the observer.Doses are based upon the weights of the animal taken prior to dosing.

METHOD

A phenylquinone writhing assay in mice was conducted over a four dayperiod to test for synergism of the analgesic activity of ibuprofen anddiphenhydramine.

The assay consists of phenyl-p-benzoquinone (PPQ) introduced in micethirty minutes post dose of the test treatment(s). The PPQ is preparedas a 0.02% aqueous solution in 5 ml ethyl alcohol q.s. to 100 ml withdistilled water and is administered intraperitoneally at 0.25 ml/mouse.The mice are injected with the PPQ solution and are placed in individualplastic squares 4"×4"×5" deep and observed for a ten minute period posttreatment dose for exhibition of the writhing syndrome. Completeblocking of the writhing syndrome for the ten minute observation periodin any one mouse is considered a positive response for that mouse.Conversely, if the mouse definitely writhes at least once, it isconsidered to be not protected from the PPQ.

Three hundred twenty-eight mice were randomly assigned to 40 groups. Twogroups of ten mice per series were assigned to a control group (10 priorto the administration of the test treatments and 10 post administration)to verify the ability of the solutions to produce the writhing response.

The purpose of the assay on the first day is to estimate the ED₅₀(effective dose in 50% of treated mice) of ibuprofen alone and ofdiphenhydramine alone, and to estimate the relative potency, ρ, ofibuprofen to diphenhydramine, determined as the ratio of the ED₅₀ ofibuprofen to the ED₅₀ of diphenhydramine. Eight mice per group are dosedorally (via intubation) with 2, 5, 10 and 20 mg/kg of ibuprofen and 5,10, 20 and 50 mg/kg of diphenhydramine. Table 1 shows the number of miceprotected from writhing activity for each dose of ibuprofen anddiphenhydramine. The method of Finney ["Statistical Method of BiologicalAssay", McMillan Pub., 3rd Edition, 1978] is used to estimate the ED₅₀'s of ibuprofen alone and diphenhydramine alone.

On the second day eight combination doses were studied. The doses werechosen based upon the ED₅₀ 's established in the preceding day'sexperiment, which, under the assumption of additivity, would provideprotection for 50% of the mice. These doses were tested in order toobserve those ratio(s) of the combination drugs that would yield asynergistic effect. Combinations for which five or more mice exhibitblockage of writhing are candidates for further study. The doses of theconstituent drugs in mg/kg for the eight groups were for ibuprofen (I)and diphenhydramine (D) respectively, [abbreviated as (I,D)]: (22,4),(19,8), (16,12), (14,6), (11,20), (9,24), (6,28), (4,32). Table 2 showsfor each of these combination doses, the number of mice protected fromwrithing activity.

On the third and fourth days the four specific fixed ratios thatachieved 5 or more protected mice were studied in more detail, i.e., thefirst combination treatment used a ratio of ibuprofen to diphenhydramineof 19:8 and the doses of the constituent drugs in mg/kg that werestudied were (8,3), (12,5), (16,7) and (28,12). The second combinationtreatment used a ratio of doses of ibuprofen to diphenhydramine of 6:28and the doses of the constituent drugs in mg/kg that were studied were(3,14), (4.5,21) and (9,42). The third combination treatment used aratio of doses of ibuprofen to diphenhydramine of 9:24 and the doses ofthe constituent drugs in mg/kg that were studied were (3,8), (6,16),(12,32) and (15,40). The fourth combination treatment used a ratio ofdoses of ibuprofen to diphenhydramine of 4:32 and the doses of theconstituent drugs in mg/kg that were studied were (3,24), (3.5,28)(4.5,36) and (5,40).

Under the assumption of additivity each dose of each combination isequivalent to a dose of ibuprofen, based on the relative potency (ρ) ofdiphenhydramine to ibuprofen obtained from the experiment on the firstday. Thus, for example, in the dose ratio 19:8 the combination of 28mg/kg of ibuprofen and 12 mg/kg of diphenhydramine is, under theassumption of additivity, equivalent to (28+12ρ) mg/kg of ibuprofen.Table 3 shows for each dose of each of the combination doses tested thenumber of mice observed to be protected and the ibuprofen equivalentdose. For each of the four combination ratios, ED₅₀ 's were estimatedbased on the observed number of mice protected at each ibuprofenequivalent dose using the method of Finney. Table 4 displays theestimated ED₅₀ 's for each ratio.

RESULTS

The surprising synergistic effects of combining ibuprofen withdiphenhydramine can be seen from the results of Tables 3 and 4 theFigure of Drawing. The Figure of Drawing summarizes all of the findingsby depicting the ED₅₀ 's obtained for each treatment alone, the ED₅₀line if the treatments were additive, the number of mice/protected fromwrithing for each treatment studied and the estimated ED₅₀ 's for eachcombination ratio.

The ED₅₀ of ibuprofen alone is estimated to be 24 mg/kg and fordiphenhydramine to be 38 mg/kg. The relative potency of diphenhydramineto ibuprofen is 24/38. Among the 8 ratios tested on the second day,synergism appears to be present for four ratios, and these ratios werefurther investigated on days 3 and 4. The ED₅₀ 's were found to be forthe dosage ratio of 19:8, 23 mg/kg of ibuprofen, for the dosage ratio6:28, 19 mg/kg of ibuprofen, for the dosage ratio 9:24, 18 mg/kg ofibuprofen, and for the dosage ratio 4:32, 23 mg/kg of ibuprofen. Two ofthese ED₅₀ 's are substantially less than 24 mg/kg of ibuprofen which isthe ED₅₀ that would be expected if the effects were additive. Thisrepresents a 25% reduction of the amount of ibuprofen that is requiredto obtain the effect in 50% of the animals. The graph in the Figure ofDrawing indicates that many other dose ratios as well would produce anunexpected synergistic effect.

                  TABLE 1                                                         ______________________________________                                        NUMBER OF MICE PROTECTED AT TESTED DOSE                                       LEVELS OF IBUPROFEN AND DIPHENHYDRAMINE                                       Dose of Dose of Di-                                                           Ibuprofen                                                                             phenhydra- Number of Mice                                                                             Number of Mice                                mg/kg   mine mg/kg Protected    Not Protected                                 ______________________________________                                         2      --         0            8                                              5      --         0            8                                             10      --         1            7                                             20      --         3            5                                             --       5         1            7                                             --      10         2            6                                             --      20         3            5                                             --      40         4            4                                             ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        NUMBER OF MICE PROTECTED AT TESTED DOSES*                                     OF THE COMBINATION OF IBUPROFEN AND                                           DIPHENHYDRAMINE                                                               Dose of Dose of Di-                                                           Ibuprofen                                                                             phenhydra- Number of Mice                                                                             Number of Mice                                mg/kg   mine mg/kg Protected    Not Protected                                 ______________________________________                                        22       4         4            4                                             19       8         5            3                                             16      12         3            5                                             14      16         4            4                                             11      20         4            4                                              9      24         5            3                                              6      28         5            3                                              4      32         5            3                                             ______________________________________                                         *Doses were chosen based upon ED.sub.50 's of ibuprofen and                   diphenhydramine which under the assumption of additivity would provide        protection for 50% of the mice.                                          

                                      TABLE 3                                     __________________________________________________________________________    NUMBER OF MICE PROTECTED AT TESTED DOSE LEVELS OF FOUR DIFFERENT RATIOS       OF DOSES OF IBUPROFEN TO DIPHENHYDRAMINE                                             Dose of                                                                             Dose of  Ibuprofen Equivalent Dose                               Combination                                                                          Ibuprofen                                                                           Diphenhydramine                                                                        Under Assumption of Additivity                                                                Number of Mice                                                                         Number of Mice                 Dose Ratio                                                                           mg/kg mg/kg    mg/kg           Protected                                                                              Not Protected                  __________________________________________________________________________    19:8   8      3        9.9            1        7                                     12     5       15.2            3        5                                     16     7       20.4            2        6                                     28    12       35.6            6        3                              9:24   3      8        8.0            2                                              6     16       16.1            2        6                                     12    32       32.2            6        2                                     15    40       40.2            8        0                              6:28   3     14       11.8            2        6                                     4.5   21       17.7            3        5                                     9     42       35.5            7        1                              4:32   3     24       18.1            2        6                                     3.5   28       21.1            3        5                                     4.5   36       27.2            6        2                                     5     40       30.2            6        2                              __________________________________________________________________________

                  TABLE 4                                                         ______________________________________                                        ED.sub.50 's OF COMBINATION TREATMENTS IN IBUPROFEN                           EQUIVALENT DOSES                                                              Tested Combination Dose Ratios                                                                    Ibuprofen Equivalent                                      of Ibuprofen to Diphenhydramine                                                                   ED.sub.50 mg/kg                                           I           D           I                                                     ______________________________________                                        100          0          24                                                    19           8          23                                                    9           24           18*                                                  6           28           19*                                                  4           32          23                                                    0           100         24                                                    ______________________________________                                         *ED.sub.50 's substantially less than 24 mg/kg, the dose that would be        expected were the effects additive.                                      

While the invention has been described and illustrated with reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various chages, modifications and substitutions can bemade therein without departing from the spirit of the invention. Forexample, effective dosages other than the preferred ranges set forthhereinabove may be applicable as a consequence of variations in theresponsiveness of the mammal treated, severity of pain or inflammation,dosage related adverse effects, if any, observed and analogousconsiderations. Likewise, the specific pharmacological responsesobserved may vary depending upon the particular relative amounts ofactive components employed or whether same are used in combination withsuitable pharmaceutical carriers, as well as the type of formulation andmode of administration employed, and such expected variations ordifferences in results are contemplated in accordance with the objectsand practices of the present invention. It is intended, therefore, thatthe invention be limited only by the scope of the claims which follow.

What is claimed is:
 1. A method for eliciting an enhanced analgesic andanti-inflammatory response in a mammalian organism in need of suchtreatment, comprising administering to such organism(i) an analgesicallyand anti-inflammatorily effective amount of diflunisal or flufenisal orpharmaceutically acceptable salt thereof, and (ii) an analgesically andanti-inflammatorily potentiating amount of diphenhydramine.
 2. A methodas defined by claim 1, wherein the component (i) comprises ananalgesically and anti-inflammatorily effective amount of diflunisal. 3.A method as defined by claim 1, wherein the component (i) comprises ananalgesically and anti-inflammatorily effective amount of flufenisal. 4.A method as defined by claim 1, comprising from about 125 mg to 500 mgdiflunisal.
 5. A method as defined by claim 1, comprising from about 125mg to 500 mg flufenisal.
 6. A method as defined by claim 1, comprisingfrom about 12.5 mg to 50 mg diphenhydramine.
 7. A method as defined byclaim 5, comprising from about 25 mg to 50 mg diphenhydramine.
 8. Amethod as defined by claim 1, wherein said composition is administeredorally.
 9. A method as defined by claim 8, wherein said composition isadministered daily in divided doses comprising from about 125 mg to 500mg diflunisal and from about 25 mg to 50 mg diphenhydramine.
 10. Amethod as defined by claim 8, wherein said composition is administereddaily in divided doses comprising from about 125 mg to 500 mg flufenisaland from about 25 mg to 50 mg diphenhydramine.
 11. A method as definedby claim 1, wherein said composition is administered orally at bedtimeas an analgesically and anti-inflammatorily effective nighttime sleepaid.
 12. A pharmaceutical composition of matter for eliciting anenhanced analgesic and anti-inflammatory response in a mammalianorganism, said composition comprising:(i) an analgesically andanti-inflammatorily effective amount of diflunisal or flufenisal or apharmaceutically acceptable salt thereof; and (ii) an analgesically andanti-inflammatorily potentiating amount of diphenhydramine.
 13. Apharmaceutical composition of matter as defined by claim 12, wherein thecomponent (i) comprises an analgesically and anti-inflammatorilyeffective amount of diflunisal.
 14. The composition of matter as definedby claim 12, wherein the component (i) comprises an analgesically andanti-inflammatorily effective amount of flufenisal.
 15. The compositionof matter as defined by claim 12, further comprising a non-toxicpharmaceutically acceptable inert carrier.
 16. A composition of matteras defined by claim 12, comprising from about 125 mg to 500 mgdiflunisal.
 17. A composition of matter as defined by claim 12,comprising from about 125 mg to 500 mg flufenisal.
 18. A composition ofmatter as defined by claim 12, comprising from about 12.5 mg to 50 mgdiphenhydramine.
 19. A composition of matter as defined by claim 12,wherein said diphenhydramine is present as the pharmaceuticallyacceptable salt thereof.
 20. A composition of matter as defined by claim12, comprising from about 125 mg to 500 mg diflunisal and from about 25mg to 50 mg diphenhydramine.
 21. A composition of matter as defined byclaim 12, comprising from about 125 mg to 500 mg flufenisal and fromabout 25 mg to 50 mg diphenhydramine.
 22. A composition of matter asdefined by claim 12, said composition being adapted for oraladministration.
 23. A composition of matter as defined by claim 12, saidcomposition being formulated as a tablet, capsule or elixir.
 24. Acomposition of matter as defined by claim 22, said composition beingadapted for oral administration in sustained release form.
 25. Acomposition of matter as defined by claim 12, said composition beingadapted for parenteral administration.
 26. A composition of matter asdefined by claim 24, said composition being formulated for intramuscularadministration.